# Effect of the antifungal drug ciclopirox on the inhibition of HMGA2-mediated oncogenic capacity in ACHN renal cell carcinoma

## TL;DR

This study explores how the antifungal drug ciclopirox can inhibit cancer cell growth by targeting HMGA2, a protein linked to tumor progression.

## Contribution

The study reveals that ciclopirox inhibits HMGA2, leading to reduced tumor cell proliferation and epithelial-mesenchymal transition in renal cancer.

## Key findings

- Ciclopirox downregulates HMGA2 and E2F1, reducing CyclinD1 and CDK6 expression in renal cancer cells.
- Ciclopirox inhibits proliferation, migration, and invasion of renal cancer cells in vitro.
- Ciclopirox suppresses tumor growth and epithelial-mesenchymal transition in vivo via the TGF-β/Smads pathway.

## Abstract

Ciclopirox olamine (CPX), an off-patent antifungal agent with a broad antimicrobial spectrum, is used to treat fungal infections. In addition to its antifungal effects, it inhibits tumor growth. However, little is known about the direct target proteins and anticancer mechanisms of CPX. The non-histone chromatin protein encoded by HMGA2, known as human high-mobility group A2, plays a crucial role in various biological processes such as cell cycle regulation, apoptosis induction, DNA damage repair, and the process of epithelial-mesenchymal transition. Increased HMGA2 expression is closely linked to tumor advancement, unfavorable prognosis, and inadequate response to therapeutic interventions. We found that CPX inhibited the level of the transcriptional regulator E2F1 in renal cancer cells by downregulating the expression of HMGA2, which led to a decrease in the expression of cell cycle protein D1 (CyclinD1) and cell cycle-dependent kinase 6 (CDK6), causing cell cycle disorders in renal cancer cells. Additionally, CPX significantly inhibited the proliferation, migration, and invasion of renal cancer cells in vitro. We also found that CPX exerted anti-tumor effects by inhibiting renal cancer cell proliferation and epithelial-mesenchymal transition (EMT) in in vivo xenograft mouse experiments. The TGF-β/Smads signaling pathway is linked to this phenomenon. These results provide robust evidence highlighting the potential for repurposing CPX in cancer treatment.